The coiled coil is a superhelical protein structural motif that consists of two or more alpha-helical peptides that are wrapped around each other in superhelical fashion. Coiled coils are amongst the most ubiquitous folding motifs found in proteins and have not only been identified in structural proteins but also play an important role in various intracellular regulation processes as well as membrane fusion. The aim of this critical review is to highlight the potential of coiled coil peptide sequences for the development of self-assembled, responsive and/or bioactive materials. After a short historical overview outlining the discovery of this protein folding motif, the article will briefly discuss naturally occurring coiled coils. After that, the basic rules, which have been established to date for the design of coiled coils will be briefly summarized followed by a presentation of several classes of coiled coils, which may represent interesting candidates for the development of novel self-assembled, responsive and/or bioactive materials. This critical review will end with a section that summarizes the different coiled coil based (hybrid) materials that have been reported to date and which hopefully will help to stimulate further work to explore the full potential of this unique class of protein folding motifs for the development of novel self-assembled, responsive and/or bioactive materials (212 references).

This manuscript reports on the self-assembly properties of two complementary peptide sequences, E3 and K3, which are derived from the known IAAL E3/K3 heterodimeric coiled coil motif. Circular dichroism spectroscopy, analytical ultracentrifugation, and fluorescence resonance energy transfer experiments indicated that a stoichiometric mixture of these two peptides forms a stable heterodimeric coiled coil at pH 7. At pH 5, in contrast, the E3/K3 heterodimeric coiled coil is unstable and unfolds to generate E3 homotrimers that coexist with K3 unimers and a small fraction of K3 homodimers. This pH-induced unfolding transition was unprecedented for this coiled coil motif but is of interest as it occurs within a physiologically relevant pH range, as it is encountered, for example, during cellular uptake via the endosomal pathway. This feature, in combination with the relatively short length of the E3 and K3 peptides and the high stability of the E3/K3 coiled coil at pH 7 makes this folding motif very attractive for the development of noncovalent polymer therapeutics and self-assembled biohybrid hydrogels.

This article reports the design, synthesis and results of first in vitro model studies of a conceptually novel class of polymer therapeutics in which the cargo is attached to a polymer backbone via a noncovalent, biologically inspired coiled coil linker, which is formed by heterodimerization of two complementary peptide sequences that are linked to the polymer carrier and the cargo, respectively. In contrast with the polymer-drug conjugates prepared so far, in which the drug is typically attached via an enzymatically or hydrolytically cleavable linker, the noncovalent polymer therapeutics proposed in this article offer several potential advantages, including facile access to combination therapeutics and rapid production of compound libraries to screen for structure-activity relationships. Furthermore, the coiled coil based peptide linkers may not only be useful to bind and release guests but may also play an active role in enhancing and directing intracellular transport and trafficking, which may make these constructs of particular interest for the cytosolic delivery of biomolecular therapeutics.

Polymer therapeutics, including polymeric drugs and polymer-protein conjugates, are clinically established as first-generation nanomedicines. Knowing that the coiled-coil peptide motif is fundamentally important in the regulation of many cellular and pathological processes, the aim of these studies was to examine the feasibility of designing polymer conjugates containing the coiled-coil motif as a putative therapeutic "molecular switch". To establish proof of concept, we prepared a mPEG-FosW(C) conjugate by reacting mPEG-maleimide (M(w) 5522 g mol(-1), M(w)/M(n) 1.1) with a FosW peptide synthesized to contain a terminal cysteine residue (FosW(C)). Its ability to form a stable coil-coil heterodimer with the target c-Jun sequence of the oncogenic AP-1 transcription factor was investigated using 2D (15)N-HSQC NMR together with a recombinantly prepared (15)N-labeled c-Jun peptide ([(15)N]r-c-Jun). Observation that heterodimerization was achieved and that the polymer did not sterically disadvantage hybridization suggests an important future for this new family of polymer therapeutics.

This paper reports on the cell uptake and trafficking properties of a series of non-covalent polymer-drug conjugates. These nanomedicines are composed of a poly(N-(2-hydroxypropyl)methacrylamide) backbone functionalized with multiple copies of a drug. The drug moieties are attached to the polymer via a non-covalent, so called coiled coil motif, which is formed by heterodimerization of two complementary peptide strands, one of which is attached to the polymer carrier and the other to the drug. Cytotoxicity and FACS experiments, which were carried out with model anticancer drug or fluorophore conjugates, provided insight into the cell uptake and trafficking behavior of these conjugates.